Mice lacking prion gene die after 70 weeks

Research into BSE and its
human equivalent Creutzfeldt-Jakob disease (CJD) continues apace as Britain and Europe
struggle to save their embattled beef industry. The latest insight into these diseases may even
have repercussions for understanding other brain-wasting diseases, such as Alzheimer's and
Parkinson's disease.

Spongiform encephalopathies are spread by a rogue form of a protein called a 'prion'. The
normal form of the protein is produced naturally in the brains of all mammals, and is
harmless -- but altered forms adopt the role of an infectious agent. Like a rotten apple, once
inside the brain, the mutant form of prion protein turns the native protein into more copies of
the deviant, infectious form. The end result is a characteristic loss of motor coordination,
dementia and death, and a brain full of holes, like a sponge. Nobody understands the
connection between prions and the particular pattern of symptoms that seem to be associated
with them, nor why the brains of infected people or animals become spongy.

As all mammals produce prion protein, it would seem likely that it serves some useful
purpose but, to everyone's surprise, mice without the prion-producing gene seem to grow up
normally into healthy adult mice. Only after seventy weeks (which is late middle-age for a
mouse) do things start to go wrong, according to Dr Suehiro Sakaguchi and his colleagues
from the Nagasaki University School of Medicine in Japan, who report their findings in the
11 April issue of Nature.

The prion-free mice were resistant to scrapie, the sheep equivalent of BSE. Just as a single
rotten apple can do no harm in an empty barrel, a brain without prion protein cannot be taken
over by the rogue form. But no-one could guess why these mice should live for so long
without feeling the deficiency of the normal prion protein.

The researchers noticed that their seventy-week-old prion-free mice were not as healthy as
they first seemed. They developed an odd, uncoordinated gait. Their back legs began to
tremble as they tried to walk, they took short tentative steps and were unable to keep a
straight path. As they got older, their coordination became progressively worse, and they
frequently collapsed. By ninety weeks, the mice had deteriorated even further. Hardly able to
stand, most had developed spasmodic arching of their backs.

These crippling symptoms are similar to those of BSE and CJD, leading the researchers to
suppose that the loss of the natural form of prion protein is to blame -- and may be the cause
of at least some cases of these diseases, even in the absence of an infectious agent. There are
two main ways in which the progressive take-over of the brain by the rogue prion might cause
disease -- either the rogue prion itself causes damage, or the loss of normal prion means its
usual beneficial function is not felt. The cerebellum, the
part of the brain responsible for movement and coordination, had shrunk by almost one-third
in the specially bred, prion-free mice.

One particular type of brain cell was particularly notable by its absence -- the Purkinje cells.
Young mice, which had not yet succumbed to illness, had healthy numbers of these cells, so
Dr Sakaguchi and his colleagues venture that prion prevents these cells from dying. After all,
old people, whose brain cells are gradually dying off, also become progressively less
coordinated in their movements. And loss of coordination is typical of many brain-wasting
diseases, including Alzheimer's and Parkinson's diseases. These Purkinje cells, it seems, can
survive for a while without any help, but they will soon die without the support of prion.
Even with it they will eventually die, but prion certainly prolongs that inevitable moment.

This latest research may also shed some light on the inherited form of CJD, a persistent
(though rare) disease. The recent frenzy in Europe came only after the reporting of several
cases of a new form of CJD. The latest victims are young people, with apparently no family
history of the disease, raising fears that the disease had been caught by eating beef infected
with BSE.

But the inherited form of CJD has long been known, affecting about one in every
million people each year. One possibility might be that those susceptible to the disease have a
faulty prion gene, so that they either do not produce enough prion, or produce it in a less
effective form.

But Dr Sakaguchi is cautious. His mice were not the first to be bred as prion-free, and those
first mice were still healthy at 93 weeks of age. Slightly different breeding techniques may
account for these differences, but until further analysis is brought to bear on prion-free mice,
researchers cannot be confident in their understanding of the prion protein. Whatever the
outcome, it will be too late to have any effect on the current economic crisis gripping Europe.

LONDON (Apr 17, 1996 4:53 p.m. EDT) -- The prion protein believed by many scientists to be responsible for mad cow disease and the related human version may also help regulate sleep, researchers reported Wednesday.

Irene Tobler of the Institute of Pharmacology at the University of Zurich and colleagues said mice bred to produce no prion proteins showed sleep disturbances and seemed unable to tell night from day properly.

"We provide evidence that the prion protein may...be involved in the regulation of sleep and that loss of this function may result in neurodegeneration in one of the prion diseases, fatal familial insomnia," they wrote in the science journal Nature.

"In mice devoid of prion protein there is an alteration in both circadian activity rhythms and sleep patterns." Circadian rhythm governs the night to day cycle of the body. Most experts think Bovine Spongiform Encephalopathy (BSE or mad cow disease) is caused by mutated prions, proteins found in the brain. Related diseases like scrapie in sheep and Creutzfeldt-Jakob Disease, kuru and fatal familial insomnia in humans are also prion- related.

The diseases are all marked by loss of memory, followed by loss of muscle coordination, weakness, and death.

Earlier this month scientists reported that mice bred to produce no prions seemed normal at first, but lost coordination and muscle control later in life.

They said this added to evidence that prions are needed for normal brain cell function.